A facile direct route to N-(un)substituted lactams by cycloamination of oxocarboxylic acids without external hydrogen

Hu Li, Hongguo Wu, Heng Zhang, Yaqiong Su (Corresponding author), Y. Song (Corresponding author), Emiel Hensen (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Lactams are privileged in bioactive natural products and pharmaceutical agents and widely featured in functional materials. This study presents a novel versatile approach to the direct synthesis of lactams from oxocarboxylic acids without catalyst or external hydrogen. The method involves the in situ release of formic acid from formamides induced by water to facilitate efficient cycloamination. Water also suppresses the formation of byproducts. This unconventional pathway is elucidated by a combination of model experiments and density functional theory calculations, whereby cyclic imines (5‐methyl‐3,4‐dihydro‐2‐pyrrolone and its tautomeric structures) are found to be favorable intermediates toward lactam formation, in contrast to the conventional approach encompassing cascade reductive amination and cyclization. This sustainable and simple protocol is broadly applicable for the efficient production of various N‐unsubstituted and N‐substituted lactams.
LanguageEnglish
Pages3778-3784
Number of pages8
JournalChemSusChem
Volume12
Issue number16
DOIs
StatePublished - 2019

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Lactams
Hydrogen
hydrogen
formic acid
Acids
acid
Formamides
drug
catalyst
Amination
water
Imines
Functional materials
Water
Formic acid
Cyclization
Biological Products
Drug products
Density functional theory
Byproducts

Cite this

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title = "A facile direct route to N-(un)substituted lactams by cycloamination of oxocarboxylic acids without external hydrogen",
abstract = "Lactams are privileged in bioactive natural products and pharmaceutical agents and widely featured in functional materials. This study presents a novel versatile approach to the direct synthesis of lactams from oxocarboxylic acids without catalyst or external hydrogen. The method involves the in situ release of formic acid from formamides induced by water to facilitate efficient cycloamination. Water also suppresses the formation of byproducts. This unconventional pathway is elucidated by a combination of model experiments and density functional theory calculations, whereby cyclic imines (5‐methyl‐3,4‐dihydro‐2‐pyrrolone and its tautomeric structures) are found to be favorable intermediates toward lactam formation, in contrast to the conventional approach encompassing cascade reductive amination and cyclization. This sustainable and simple protocol is broadly applicable for the efficient production of various N‐unsubstituted and N‐substituted lactams.",
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A facile direct route to N-(un)substituted lactams by cycloamination of oxocarboxylic acids without external hydrogen. / Li, Hu; Wu, Hongguo ; Zhang, Heng; Su, Yaqiong (Corresponding author); Song, Y. (Corresponding author); Hensen, Emiel (Corresponding author).

In: ChemSusChem, Vol. 12, No. 16, 2019, p. 3778-3784.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Li,Hu

AU - Wu,Hongguo

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AU - Song,Y.

AU - Hensen,Emiel

PY - 2019

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AB - Lactams are privileged in bioactive natural products and pharmaceutical agents and widely featured in functional materials. This study presents a novel versatile approach to the direct synthesis of lactams from oxocarboxylic acids without catalyst or external hydrogen. The method involves the in situ release of formic acid from formamides induced by water to facilitate efficient cycloamination. Water also suppresses the formation of byproducts. This unconventional pathway is elucidated by a combination of model experiments and density functional theory calculations, whereby cyclic imines (5‐methyl‐3,4‐dihydro‐2‐pyrrolone and its tautomeric structures) are found to be favorable intermediates toward lactam formation, in contrast to the conventional approach encompassing cascade reductive amination and cyclization. This sustainable and simple protocol is broadly applicable for the efficient production of various N‐unsubstituted and N‐substituted lactams.

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